Diquaternary ammonium salts of n, n, n&#39;, n&#39;-tetra substituted alkylene diamines



United States Patent Ofifice Patented Jan. 1, 1963 3&7 11,618 DIQUATERNARY AMMGNEUM SALTS F N,N,N', N-TETRA SUBSTITUTED ALKYLENE DIAMINES Ellis Rex Pinson, .lr., Jackson Heights, N.Y., assiguor to Chas. Pfizer & (30., Inc, Brooklyn, N.Y., a corporation of Delaware No Drawing. Filed Feb. 2, 1956, Ser. No. 562,937

h (Ilairns. (Cl. 26t)567.6)

This invention is concerned with a new class of highly effective therapeutic agents and the process by which they are prepared. In particular, the therapeutic agents of this invention are diquaternary ammonium salts of a group of N,N,N,N-tetra substituted alkylene diamines. These diquaternary ammonium salts have proved to be valuable in the therapy of hypertension.

The compounds of this invention may be defined as N-aralkyl, N,N-fully substituted alkylene compounds with pharmacologically acceptable anions, the alkylene chain containing up to and including five carbon atoms in a straight chain between the two nitrogen atoms; the N aralkyl substituents being selected from the group consisting of benzyl, l-naphthyl-methyl, l-indanyl and 9-fiuorenyl groups; the remaining substituents on the N-atom being alkyl groups each containing up to and including three carbon atoms; the N substituents being alkyl groups each containing up to and including three carbon atoms. It is specifically intended to include within the scope of this invention compounds in which two of the alkyl groups on the N atom are joined and together with the nitrogen atom to which they are attached form a saturated heterocyclic ring such as pyrrolidine or piperidine, and further compounds in which the alkyl groups are joined through oxygen and together with the nitrogen atom to which they are attached form a morpholine ring.

In order to further illustrate the compounds which it is intended to include within the purview of this invention the following structural formula is presented:

wherein Alk is a lower alkylene group which contains from two to five carbon atoms in the straight chain between the two quaternary nitrogen atoms; R and R are selected from the group consisting of alkyl groups containing up to and including three carbon atoms, and further groups wherein R and R are joined and together With the nitrogen atom to which they are attached form a heterocyclic ring such as pyrrolidine, piperidine or morpholine. R R and R are lower hydrocarbon alkyl groups each containing up'to and including three carbon atoms. X is selected from the group consisting of substituted and unsubstituted benzyl groups, substituted and unsubstituted l-naphthyl-methyl groups; substituted and unsubstituted l-indanyl groups, and substituted and unsubstituted 9-fluorenyl groups; and A is a pharmacologically acceptable anion.

In the foregoing structural formula lAlk is a lower hydrocarbon alkylene group in which the number of carbon atoms in the straight chain between the two quaternary nitrogen atoms is a number up to and including five. Representative compounds of this type include N-benzyl- N,N,N-trimethylethanediamine dimethiodide; N-benzyl- N,N,N-trimethyl-1,3-propanediarnine dimethiodide; N- benzyl N,N,N,2 tetramethyl 1,3 propanediamine dimethiodide; N benzyl N,N,N-trimethyl-2-ethyl-l,3- propanediamine dimethiodide; N-benzyl-N,N,N'-trimethtetramethyl-l,4-butanediamine dimethiodide; N-beuzyl-N,

N',N-trimethyl-l,S-pentandiarnine dimethiodide; and N- benzyl-N,N',N,3-tetramethyl-1,5-pentanediamine dimethiodide.

In the foregoing structural formula R and R are selected from the group consisting of alkyl groups each containing up to and including three carbon atoms and further groups where two of said R and R groups taken with the nitrogen atom to which they are attached form a heterocyclic ring, preferably saturated, such as pyrrolidino, piperidino and morpholino. Representative compounds of this type include N-benzyl-N,N-dimethyl-N- ethylethanediamine dimethiodide; N-benzyl-N,N',N,1- tetramethylethanediamine dimethiodide; N benzyl N- methyl N',N-diethyl-1,3-propanediamine dimethiodide; N-benzyl-N,N-dimethyl-N-propylethanediamine dimethiodide; N-benzyl-N,N,3-trirnethyl-N'-propyl-1,5-pentanediamine dimethiodide; N-benzyl-N-methyl-N ethyl-N'- propyl 1,4-butanediamine diethiodide; l-(benzylmethylamino)-3-morpholinopropane dimethiodide; l-(benzylmethylamino)-4-morpholinobutane diethiodide; l-(benzylmethylamino)-2-pyrrolidinoethane dimethiodide; and 1 (benzylmethylamino) S-pyrrolidinopentane dipropiodide.

In the foregoing structural formula R R and R are lower hydrocarbon alkyl groups each containing up to and including three carbon atoms. Representative compounds of this type include N-benzyl-N-ethyl-N',N-dimethylethanediamine dimethiodide; N-benzyl-N-propyl-N,N'- dimethylethanediamine dimethiodide; N-benzyl-N-ethyl- N',N,2-trimethyl-1,3-propanediamine diethiodide; N-benzyl-N-ethyl-N,N-dimethyl-1,4 butanediamin-e dipropiodide N benzyl N methyl N,N'-diethyl-1,S-pentanediamine dipropiodide; and N-(1-naphthylmethyl)-N-ethyl- N'N',3-trimethyl-1,5-pentanediamine dipropiodide.

In the foregoing structural formula X is selected from the group consisting of substituted and unsubstituted benzyl groups; substituted and unsubstituted l-naphthylmethyl groups; substituted and unsubstituted l-indanyl groups and substituted and unsubstituted 9-fluoroenyl groups. This substitution may be on the ring, that is to say, it may be cyclic substitution; and the substituents, which may be singular or multiple, may be in any position relative to each other and are chosen from the group consisting of halogen atoms, alkyl groups each preferably containing up to and including four carbon atoms, alkoxy groups each preferably containing up to and including four carbon atoms, and phenyl groups. In the case where X represents the benzyl or the l-naphthyl-methyl group, the substitution may be exocyclic as Well as cyclic, that is to say, substitution can be on the a carbon atom. In this case, the substituent is chosen from the group consisting of lower hydrocarbon alkyl groups each preferably con taining up to and including four carbon atoms and substituted and unsubstituted phenyl groups. Representative compounds of this type include N-benzyl-N,N,N-trimethylethanediamine dimethochloride;

N-( 3-chlorobenzyl -N,N',N-trimethylethanediamine dimethochloride;

N- 4-tert-butylbenzyl) -N,N',N'-trimethylethanediamine dimethochloride;

N-( 3-chlorobenzyl) N,N',N-trimethyl-l,4-butanediamine dimethochloride;

N- 4-tert-butylbenzyl) -N,N,N,2-tetramethyl-l ,5-

pentanediamine dimethochloricle;

N-( l-naphthylmethyl) -N,N',N-trimethylethanediarnine dimethiodide;

N-( l-naphthylmethyl -N,N',N'-trimethylethanedi amine dimethochloride;

N-( 4-methyll-naphthylmethyl -N,N,N-trimethylethanediamine dimethiodide;

N-( l-naphthylmethyl -N,N ,N'-trimethyl-1,4-

butanediamine dimethochloride;

N-( l-naphthylrnethyl) -N,N',N-trimethyl-1,5-

pentanediamine dimethiodide;

N4( l-naphthylmethyl)-N,N',N',3-tetramethyl-1,5-

pentanediamine diethiodide;

N-( l-indanyl -N',N',dimethylethanediamine dimethochloride;

N-( l-indanyl) -N',N'-dimethyl-1,4-butanediamine dimethobromide;

N-9-fluoroenyl-N,N'-dimethyleth-anediamine dimcthochloride;

N-(4,4'-dichlorobenzhydryl -N,N',N-triethyl-l ,5-

pentanediamine dirnethochloride;

N- a,4-dimethylbenzyl) -N,N,N'-trimethyl-1 ,4-

butanediamine dimethochloride;

N-( a-ethyl-l-naphthylmethyl) -N,N',N'-trimethylethanediamine dimethobromide; and

N( a-ethyl-4-ethoxybenzy1) -N,N',N-trirnethyl- 1 ,4-

butanediamine dimethochloride.

In the foregoing structural formula A is a pharmacologically acceptable anion such as iodide, chloride, bromide, sulfate, methylsulfate, acetate, proponate, tartrate, citrate, gluconate, etc. The term, pharmacologically acceptable anion has a definite meaning to one skilled in the art. It is defined as a non-toxic anion of any of the simple acids commonly used in pharmacology to neutralize basic medicinal agents when the salt thereof is to be used therapeutically. The pharmacological activity of the molecule is primarily a function of the cation, the anion serving chiefly to supply electrical neutrality.

As might be expected, certain of them are more active than others-for example, better activity is found if the alkylene, here represented by Alk, between the two nitrogen atoms contains in a straight chain either two or three carbon atoms. Again, better activity is evident when the alkyl groups R R R R and R are a combination of methyl and ethyl groups with the majority being methyl groups.

These agents may be administered alone or in combination with pharmaceutically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets or capsules containing such excipients as starch, milk sugar, certain types of clay, etc. They may be administered sublingually in the form of troches or lozenges in which the active ingredient is mixed with sugar and corn syrups, flavoring agents and dyes; and then dehydrated sul'ficiently to make it suitable for pressing into a solid form. They may be administered orally in the form of solutions which may contain coloring and flavoring agents or they may be injected parenterally, that is, intramuscularly, intravenously or subcutaneously. For parenteral ad ministration they may be used in the form of a sterile solution containing other solutesfor example, enough saline or glucose to make the solution isotonic.

The physician will determine the dosage which will be most suitable and it will vary with the form of administration and the particular compound chosen, and furthermore, it will vary with the particualr patient under treatment. He will generally wish to initiate treatment with small dosages substantially less than the optimum dose of the compound and increase the dosage by small increments until the optimum effect under the circumstances is reached.

The diquaternary ammonium salts of this invention are prepared by quaternizing the appropriate diamines. These diamines can be prepared by a number of methods.

In one of the routes by which these diamines are prepared an appropriate aromatic aldehyde or ketone is reacted with a diamine under reducing conditions, for example, with hydrogen in the presence of a suitable catalyst such as a noble metal catalyst or nickel. The

aromatic aldehyde or ketone reacts with the amine so that a hydrogen on the nitrogen atom is replaced with an aryl or alkaryl group. If desired, a second hydrogen on the nitrogen atom is replaced by reaction with a carbonyl compound in the presence of a reducing agent, for example, formic acid. An example of this reaction is shown below.

+ nmcmommonm T CH2lTICHzCH2N (CH 3 In an alternative route to the diamines an aromatic acid chloride is reacted with a diamine. The acid chloride reacts to form an amide. The amide is reduced using hydrogen and a noble metal catalyst, or in a preferred embodiment of the reaction, preferred because it gives a higher yield, the reducing agent is lithium aluminum hydride. If desired, an additional alkyl group can be introduced by reacting the amine with a carbonyl compound in the presence of a reducing agent, for example, formic acid. An example of this reaction is shown below.

In another method by which these diamines are prepared an aromatic aldehyde or ketone is reacted with a primary amine under reducing conditions-for example, hydrogen in the presence of a noble metal catalyst. The resulting tertiary amine is condensed under basic conditions with a dialkylamino substituted alky-l halide. This reaction is shown below.

CHO

CH2NCH3 niN OH;

CHzNCH;

H (CH3)2NCH2CHZC1 There are, of course, other methods by which these diamines can be prepared and they will occur to those skilled in the art.

The valuable diquarternary ammonium salts of this invention can be prepared by treatment of the appropriate diamine with a quaternizing agent such as an alkyl halide, sulfate or sulfonate ester either in the presence or absence of an organic solvent. The diamine is selected from the group consisting of those diamines having the formula:

parent that the diamine can be disecondary, ditertiary, monoprimary monosecondary, monoprimary monotertiary, or rnonosecondary monotertiary.

For conversion to the diquaternary salts the diamine, if a ditertiary type, is treated directly with the quaternizing agent. It the diamine is of any of the other types described above, it is treated with an excess of the quater nizing agent under alkaline conditions such as alcoholic sodium carbonate and sodium bicarbonate.

Examples of both of these reactions are shown below:

/CH3 CHzNCH2CHz-N 6211501 2H5 CH3 t f oI}NHzGHalTI C2115 C2116 C2115 CH3 base CHs1TTCHaCHzN on ol (B1 C1 C2115 CHzNCHzC/H2N CH3 CH3 a C2Ha In the above example quaternary alkyl chlorides are prepared. It is, of course, likewise possible to prepare quaternary alkyl iodides, bromides, or methosulfates.

These compounds may be converted to the quaternary salts of other acids by a number of methods. Thus on treatment of the quaternary halide with an aqueous solution of the silver salt of another acid such as silver nitrate or silver acetate, the silver halide is precipitated and the diquaternary dinitrate or diacetate is formed. Alternatively, the quaternary halide or methosulfate may be converted to the quaternary hydroxide using silver oxide. The quaternary hydroxide thus obtained may be con verted to the desired salt by titration with an acid.

A further method which is highly useful for this purpose comprises contacting the quaternary halide with the basic anion exchange resin, preferably a highly basic compound such as the Rohm & Haas compound Amberlite IRA-400 in the basic form. This resin is a polyquaternary ammonium compound which is prepared by chloromethylating a highly cross-linked copolymer of styrene and divinyl benzene and treatment of the chloromethylated material with a tertiary amine such as trimethylamine. By use of this resin a quaternary ammonium hydroxide corresponding to a salt of this invention 'is formed. It is then neutralized with the appropriate acid. For instance, citric acid, tartaric acid, propionic acid, acetic acid, nitric acid, sulfuric acid, etc. Alternatively, the resin may be converted to the acid whose quaternary salt is desiredfor example, the tartrate. The tartrate resin is then contacted with the diquaternary halide in aqueous solution, and an anion exchange takes place converting the quaternary halide to the tartrate and leaving the halide ion on the resin. The tartrate salt can then be recovered from the eluate by a number of methods such as evaporation or solvent precipitation.

Other methods by which these valuable diquaternary compounds can be prepared will occur to those skilled in the art.

The following examples are given by way of illustration and are not intended to limit the scope of the invention. In fact, many Widely varying embodiments are possible Without departing from the spirit and scope of the herein described invention. It is to be understood that this in- 7 vention is to be limited only by the specific wording of the appended claims.

In the following examples all temperatures are given in degrees centigrade.

EXAMPLE I N -(3,4-Dichlr0benzyl -N ,N '-Dimethylethanediamine A solution of 52.5 g. (0.3 mole) of 3,4-dichlorobenzaldehyde and 26.4 g. (0.3 mole) of 1-dimethylamino-2- aminoethane in 150 ml. of absolute ethanol is hydrogenated over a catalyst prepared by reducing 0.50 g. of platinum oxide in 50 ml. of absolute ethanol. The calculated amount of hydrogen is taken up after reduction at 3 atmospheres pressure at 30 C. for 12 hours. The catalyst is filtered OE and the ethanol removed by distillation in vacuo. The residue, a yellow oil, is dissolved in 200 ml.

of 3 N hydrochloric acid and the solution extracted three times with 50 m1. portions of chloroform to remove nonbasic material. The aqueous phase is made strongly alkaline with 30% sodium hydroxide and the yellow oil which separated removed by extraction with chloroform. The chloroform extract is dried over anhydrous potassium carbonate, filtered through a Supercel pre-coated funnel and concentrated in vacuo to 53.2. g. of a viscous yellow oil. Distillation of this oil yields 48.2 g. of the desired product B.P. 125133 C./0.5-1.0 mm; n =1.5361; d =1.138. The hydrobromide crystallizes in colorless plates from absolute ethanol, M.P. 219.6-220.4.

ANALYSIS: CnHmNzCIzBrz ethanediamine is chilled in an ice bath and 310 ml. of 88% formic acid is added slowly with good stirring. This solution is heated to 60 on a steam bath and 220 ml. of 40% formalin is added slowly. The mixture is boiled under reflux for 18 hours, cooled and acidified with 320 ml. of concentrated hydrochloric acid. The acid solution is concentrated to a small volume in vacuo and made strongly alkaline with 30% sodium hydroxide. The yellow oil which separates is removed by extraction with chloroform. The chloroform solution is dried over anhydrous potas sium carbonate, filtered through a Supercel pre-coated funnel and concentrated in vacuo, yielding 41.1 g. of a yellow oil. Distillation of the oil yields 35.7 g. of the N-(3,4- dichlorobenzyl) N,N',N' trimethylethanediamine, B.P. 119-130" C./0.5-0.75 mm; n =1.5285; d =1.125. The hydrobromide crystallizes in colorless microcrystals from methanol, M.P. 248.0-248.4.

ANALYSIS: Ci2H2oN2C12Br2 Found Calculated Carbon..- 34. 32 34. 07 Hydr0gen 4. 87 4. 77 Nitrogen 6. 37 6. 62

EXAMPLE III N- (S-Dimethylaminopropyl) -p-Tert-Butylbenzamide ANALYSIS 2 C i7Hz9NgOI Calculated Carbon Hydrogen...

EXAMPLE IV N-(p-TertButylbenzyl)-N,N'-Dimetlzyl-1,3- Propanediamine A solution of lithium aluminum hydride is prepared by dissolving 7.6 g. (0.2 mole) of the solid in 750 ml. of absolute ether. A solution of 25 g. (0.1 mole) of the benzamide, prepared as in Example III in 150 ml. of absolute ether is added dropwise to the stirred lithium aluminum hydride at a rate sufiicient to maintain gentle reflux. The mixture is refluxed for an additional 3 hours and allowed to stand overnight. The excess lithium aluminum hydride and product complex is decomposed by the dropwise addition of 20 ml. of water with good stirring. The precipitated aluminum is filtered off and washed twice with 300 ml. portions of ether. The ether solution is dried over anhydrous magnesium sulfate and concentrated in vacuo to a colorless oil which is not purified further but is characterized through its hydrobromide. The hydrobromide crystallizes in small colorless plates from. isopropyl alcohol, M.P. 242-244 d.

ANALYSIS: CwHao z n Found Calculated Carbon 46. 46. 84 Hydrogen 7. 69 7. 37

EXAMPLE V N-(p-Tert-Butylbenzyl)N,N',N'-Trimethyl-1,3- Propanediamine 15 g. of the propanediamine from Example IV is methylated using the procedure given in detail in Example II for the 3,4-dichlorobenzyl derivative. A-fter distillation there is obtained 13.8 g. of a colorless oil, B.P. 118-124 C./0.25 mm. The product is characterized through its dimethiodide which crystallizes in colorless needles from ethanol-ethyl acetate, M.P. 200-201 C.

A solution of 34 g. (0.2 m.) of veratraldehyde and 12 g. (0.4 m.) of methylamine in ml. of absolute ethanol is hydrogenated over a catalyst prepared by reducing 0.50 g. of platinum oxide in 50 ml. of absolute ethanol. The calculated amount of hydrogen is taken up after a reduction at 3 atmospheres pressure at 25 for 3 hours. The residue is dissolved in 200 ml. of 3 N HCl and the solution extracted three times with 50 m1. portions of chloroform to remove non-basic material. The aqueous phase is made strongly alkaline with 30% sodium hydroxide ANALYSIS: C HmNozBr Found Calculated Carbon 45. 72 45. 81 Hydrogen 6. 18 6. 15 Nitro en 5. 16 5. 34 Bromine 30. 37 30. 49

EXAMPLE VII N (3,4-Dimethxybenzyl)-N,N,N'-T rimethylethanediamine Dihydrochloride A solution of 0.12 m. of 1-chloro-2-dimethylaminoethane in 150 ml. of isopropyl alcohol is prepared by dissolving 17.6 g. of the compound as the hydrochloride in 61 ml. of ice cold saturated aqueous potassium carhonate and extracting three times with 50 ml. portions of ice cold isopropyl alcohol. The combined isopropyl alcohol solutions are dried briefly over anhydrous potassium carbonate and filtered through glass wool. This solution is added with good stirring to a solution of 20 g. (0.13 m.) of veratrylmethylamine prepared as described in Example VI in 100 ml. of isopropyl alcohol at 0 C., stirred 18 hours, and'acidified to pH 1 with concentrated hydrochloric acid. The hydrochloride which precipitated is obtained by filtration and Weighed 24.7 g. An additional 5.3 g. of hydrochloride is obtained by concentrating the isopropyl alcohol solution. After recrystallization from 95% ethanol the purified hydrochloride melts at 268.4269.8 C. with decomposition.

EXAMPLE VIII N-Benzyl-N,N,N-Trimethylethanediamine Dimethiodide ANALYSIS: Ci4H2i 2I2 Found Calculated Carbon 35. 29 35.31 Hydrogen 5. 66 5. 50

EXAMPLE IX N-(4-Tert-Butylbenzyl) -N,N',N'-Trimethyl-1,3- Propanediamine Dimethiodide 26.2 g. (0.1 m.) of N-(ptert-butylbenzyl)-N,N,N- trimethyl-l,3-propanediamine is treated exactly as in Example VIII to give 53 g. of material which when recrystallized from ethanol-ethyl acetate melts at 200- 201 C.

EXAMPLE X N-(1-Indanyl-) -N,N'-Dimethyl-1,3Pr0panediamine This compound was prepared from 0.3 mole of 1- indanone and 0.3 mole of 1-amino-3-dimethylaminopropane using the procedure of Example I. The compound was used directly for the preparation of N-(l-indanyD- N,N',N-trimethylpropanediamine (Example XI).

1 0 EXAMPLE XI N (1 Jndanyl)-N,N',N-Trimethyl-1,3-Propanediamine This compound is prepared using the procedure of Example II. It is an oil boiling at 135 C./0.5 mm. It is converted to the dihydrobromide and recrystallizes from absolute ethanol, M.P. 230.4230.8 d.

ANALYSIS: C H NzBm Found Calculated Carbon 45. 48 45. 70 Hydrogen 6. 93 6. 65

EXAMPLE XII N-(1 -Indanyl) -N,N,N-Trimethyl-1,3-Propanediainine Dimethiodide This compound is prepared using the procedure of Example VIII. It recrystallizes from absolute ethanol, M.P. 282283 C. d.

ANALYSIS: C17H3ON2I2 Found Calculated Carbon 39. 35 39. 35 Hydrogen 5. 88 5.

EXAMPLE XIII EXAMPLE XIV 1-(3,4-Dichlorobenzylamino)-2-Pyrrolidinoethane This compound is prepared from 3,4-dichloroben2aldehyde and 1amino-2-pyrrolidinoethane using the procedure of Example I.

EXAMPLE XV 1 (3,4-Dichl0r0benzy lmethylamino -2 -Pyrrolidinoerhane This compound is prepared from the product of Example XIV using the procedure of Example II.

EXAMPLE XVI 1-(3,4-Diclzlor0benzylmethylamino)-2-Pyrr0lidinoethane Dimethiodia'e This compound is prepared from the product of Example XV using the procedure of Example VIII.

EXAMPLE XVII J-(S-Chlorobenzylamino) -3 Piperidin0pr0pane This compound is prepared from 3-chlorobenzaldehyde and 1amino-3-piperidinopropane using the procedure of Example I.

EXAMPLE XVIII 1- (3-Chlorobenzylmethylamino) -3-Piperidil10pr0pane This compound is prepared from the product of Example XVII using the procedure of Example II.

EXAMPLE XIX 1-(3-Chlorobenzylmethylamino)-3-Piperidinopr0pane Dimethobroniide This compound is prepared from the product of Example XVIII using the procedure of Example VIII.

1 1 EXAMPLE XX l-(3,4-Dimethylbenzylamino)-2-M0rph0lin0ethane This compound is prepared from 3,4-dimethylbenzaldehyde and 1-amino-2-morpholinoethane using the procedure of Example I.

EXAMPLE XXI 1(3,4-Dimethylbenzylmethylamina -2-M0rpholin0ethane This compound is prepared from the product of Example XX using the procedure of Example II.

EXAMPLE XXII 1-(3,4-Dimethylbenzylmethylamino)-M0rph0lin0ethane Dimethiodide This compound is prepared from the product of Example XXI using the procedure of Example VIII.

EXAMPLE XXIII N-(l -Naphthylmethyl) -N',N'-Dimethylethanediamine This compound is prepared from tx-naphthaldehyde and 1-amino-2-dimethylaminoethane using the procedure of Example I. It is an oil which is not further purified, but is used directly in the preparation of the product of Example XXIV.

EXAMPLE XXIV N-(1-Naplzthylmethyl)-N,N',N'-Trimethylethwnediam'ine This compound is prepared from the product of Example XIII using the procedure of Example II. It is an oil; B.P. l38140/0.5 mrn., n =l.5696.

For analysis a dihydrobromide is formed; M.P. 245- 246 d.

ANALYSIS: CIBHZ4N2BYZ Found Calculated Bromine 39. 51 39. 55

EXAMPLE XXV N-(I-Naphthylmethyl)-N,N',N-Trimethylethanediamine Dimethiodide This compound is prepared from the product of Example XXIV using the procedure of Example VIII. The compound melts at ZOO-201 d.

ANALYSIS: CrsHzsNzIa Calculated Carbon Hydrogen Nitrogen EXAMPLE XXVI N (9-Flu0renyl -N ,N ,N '-Trimethylethanediamine-N M ethobromidc A solution is prepared containing 10 g. of 9-bromofluorene and 71 g. of tetramethylethanediamine in absolute ethanol. After standing for forty-eight hours white needles precipitate out of solution, and are obtained by filtration. The Weight is 11.68 g. Another crop of crystals is obtained by treating the alcohol solution with two volumes of ether. The crystals are triturated with ether, dried in vacuo and melt at 115-116.8.

EXAMPLE XXV II N -(9-Flu0renyl -N,N ,N -T rimethylethanediamine Dimethobromide This compound is prepared from the product of Example XXVI using the procedure of Example II. The diquatemary compound which is obtained by filtration from 12 the acetonitrile is washed with acetone and dried in vacuo; M.P. 155.4157 d.

For analysis a small amount of the diquaternary salt is dissolved in water. The insoluble inpurities are filtered free and the product obtained by freeze drying the solution.

ANALYSIS: czoHzs zBrz Found Calculated Bromine 34. 84 35. 03

EXAMPLE XXVIII N -Benzhydryl-N,N ',N -T rimethyIezlmnediamine-N Methobromide This compound is prepared from benzhydryl bromide and tetra-methylethanediamine using the procedure of EX- ample XXVI.

EXAMPLE XXIX N-benzhydryl-N,N,N'-Trimethylethanediamine Dimethobromide This compound is prepared from the product of Example XXVIII using the procedure of Example VIII.

EXAMPLE XXX N -(ot-Ethyl-4-Clzl0r0benzylidine) -N ,N -Dimethyl-1 ,3- Propanediamine A benzene solution cc.) containing 16.9 g. (0.1 m.) of 4-chloropropiophenone and 11.22 g. (0.1 m.) of 1-amino-3-dimethylaminopropane is refluxed for two days while water is removed as an azeotrope with benzene. The solution is cooled and the benmne removed in vacuo. The product is not purified, but is used directly for the preparation of the product of Example XXXI.

EXAMPLE XXXI N a-Ethyl-4-Chl0robenzyl -N ',N -Dim ethyl-1 ,3 Pmpanediamine precipitates is extracted three times with chloroform.

The combined extracts are dried over anhydrous potassium carbonate, the drying agent filtered off, and the solvent removed in vacuo. The product is not further purified, but is used directly in the preparation of the product of Example XXXII.

EXAMPLE XXXII N-(u-Ethyll-Chlorobenzyl)-N,N',N-Trimethyl-1,3 Propanediamine This compound is prepared from the product of Example XXXI using the procedure of Example II. It is an 011; RP. -l22/0.03 mm., n =l.5123.

EXAMPLE XXXIII N-(ot-Ethyl-4-Chlorobenzyl) -N,N',N'-Trimethyl-l,3- Propanediamine Dimethobromide This compound is prepared from the product of Example XXXII using the procedure of Example VIII. It melts at 141-142 d.

ANALYSIS: CnHarNzClBrz Found Calcula ted Bromine EXAMPLE XXXV N-(cz-Methyl-4-Chlorobenzyl) -N,N',N'-Trimethyl-1,3- Propanediamine This compound is prepared from the product of Example XXXIV using the procedure of Example II. It was not purified, but was used directly in the preparation of the product of Example XXXVI.

EXAMPLE XXXVI N- a-Merhyl-4-Ch lorobenzyl) -N,N,N-Trim ethyl-1,3- Propanediamz'ne Dimethiodide This compound is prepared from the product of Example XXXV using the procedure of Example II. It is recrystallized from absolute ethanol and melts at 200 201 (1.

ANALYSIS: CieHzaN2C11I2 Found Calculated Carbon 35, 96 35. 67 Hydrogen 5. 56 5. 43

The following list is a representative sampling of some of the compounds of this invention which have been prepared.

Melting point, Compounds:

N benzyl N,N,N' trimethylethanecliamine dimethiodide N benzyl N methyl N,N diethylethanediamine dimethiodide 188-189 N benzyl N,N',N' trimethyl 1,3-

propanediamine dimethobromide 124-125 N (4 tert butylbenzyl) N,N,N'-trimethyl 1,3 propanediamine dimethiodide 200-201 N (3,4 dirnethoxybenzyl) N,N,N-trimethylethanediamine dimethiodide 185-l86 N (4 chlorobenzyl) N methyl -N',N-

diethylethanediarnine dimethiodide 202203 N (c methyl 4 chlorobenzyl) N- rnethyl N',N diethylethanediamine dimethiodide 187-188 N-(u-methyl 4 chlo1'obenzyl)- I,N,l I-

trimethyl 1,3-propanediarnine dimethiodide 2OO201 N (3,4 dichlorobenzyl) N,N,N*trimethylethanediamine dimethochloridm- 214-215 N (3,4 dichlorobenzyl) N,N',N-trirnethylethanediarnine dimethiodide 212-213 N (3,4 dichlorobenzyl) N,N' dimethyl N ethylethanediamine dimethobrornide 202-203 N (3,4 dichlorobenzyl) N ethyl -N,

N dirnethylethanediamine dimethiodide 201-202 N (3,4 dichlorobenzyl) N,N,N' trimethylethanediamine diethobromide 204-205 N (3,4 dichloro benzyl) N methyl N,N' diethylethanediamine dimethiodide 183-184 degrees centigrade 14 N (3,4 dichlorobenzyl) N,N,N'-trimethyl 1,3 propanediamine-dimethiodide N (wmethyl-p-phenylbenzyl) N,N,N"- trimethyl 1,3 propanediamine dimethobromide N (oc,3,4 trimethyl'benzyl) N,N,N'- trimethyl 1,3 propanediamine dimethobromide N (a ethyl 4 chlorobenzyl) N,N',

N trimethyl 1,3 propanediamine di methobromide N (2,4 dichlorobenzyl) N,N',N'-trimethyl 1,3 propanediamine dimethobromide N (9 fluorenyl) N,N,N' trimethylethanediamine dimethobromide N (1 naphthylrnethyl) N,N,N' trirnethyl 1,3 propanediamine dimethobromide 212-213 N (1 naphthylrnethyl) N,N',N' trimethylethanediamine dimethiodide 1 Decomposed.

What is claimed is: 1. A diquaternary ammonium compound having the formula:

ARi

wherein:

a. X is selected from the group consisting of benzyl groups l-naphthylmethyl groups, l-indanyl groups and 9-fluorenyl groups;

11. Alk is a lower hydrocarbon alkylene group wherein the number of carbon atoms in a straight chain between the two nitrogen atoms is a number from two to three inclusive;

0. R and R are selected from the group consisting of alkyl groups containing up to three carbon atoms, and further groups wherein R and R are joined and together with the nitrogen atom to which they are attached form a heterocyclic ring selected from the group consisting of pyrrolidine, piperidine and morpholine heterocyclic rings;

d. R R, and R are selected from the group consisting of lower alkyl groups containing up to three carbon atoms;

e. A is a pharmacologically acceptable anion.

2. N '(3,4-dichlorobenzyl) N,N',N' trimethyl-1,3-

propanediamine dimethiodide.

3. N (l-naphthylmethyl) N,N',N'-trimethylethanediarnine dimethiodide.

4. N (4-tert-butylbenzyl) N,N',N' trimethyl 1,3- propanediamine dimethiodide.

5. N (a-methyl-4-chlorobenzyl) N methyl I',N'- diethylethanediamine dimethiodide.

6. N (a,3,4trimethylbenzyl) 'N,N',N' trirnethyl- 1,3-p1'opanediamine dimethobromide.

7. A process for the preparation of an N,N,N,N' tetrasubstituted diquaternary ammonium compound which comprises treating an amine with a quaternizing agent selected from the group consisting of alkyl halides, alkyl sulfates and alkyl sulfonate esters, the amine being selected from the group of those amines having the structural formula:

wherein:

a. X is selected from the group consisting of benzyl groups, l-naphthylmethyl groups, l-indanyl groups and Q-fiuorenyl groups;

b. Alk is a lower hydrocarbon alkylene group wherein the number of carbons in a straight chain between the two nitrogen atoms is a number from two to three inclusive;

0. R and R are selected from the group consisting of alkyl groups containing up to three carbon atoms and further groups wherein R and R are joined and together with the nitrogen atom to which they are attached form a heterocyclic ring selected from the group consisting of pyrrolidine, piperidine and morpholine rings;

d. R is selected from the group consisting of lower alkyl groups containing, up to three carbon atoms.

Rs R1 wherein a. X is selected from the group consisting of benzyl groups, l-naphthylmethyl groups, l-indanyl groups and 9-fiuorenyl groups;

b. Alk is a lower hydrocanbon alkylene group Wherein the number of carbons in a straight chain becompound 1 6 tween the tWo nitrogen atoms is a number from two to three inclusive;

c. R and R are selected from the group consisting of the hydrogen atom and alkyl groups containing up to three canbon atoms and further groups wherein R and R are joined and together with the nitrogen form a heterocyclic ring selected from the group consisting of pyrrolidine, piperidine and morpholine rings;

d. R is selected from the group consisting of the hydrogen atom and lower alkyl groups containing up to three carbon atoms.

9. The compound of the formula:

01 I CH (EH CH 01 CH5 CH3 01 References Cited in the file of this patent UNITED STATES PATENTS Kyrides V Apr. 7, 1953 OTHER REFERENCES 

1. A DIQUATERNARY AMMONIUM COMPOUND HAVING THE FORMULA: 